ALEXANDRE FERREIRA RAMOS
Projetos de Pesquisa
Unidades Organizacionais
SIN-86, EACH - Docente
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina
5 resultados
Resultados de Busca
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- Binary Expression Enhances Reliability of Messaging in Gene Networks(2020) GAMA, Leonardo R.; GIOVANINI, Guilherme; BALAZSI, Gabor; RAMOS, Alexandre F.The promoter state of a gene and its expression levels are modulated by the amounts of transcription factors interacting with its regulatory regions. Hence, one may interpret a gene network as a communicating system in which the state of the promoter of a gene (the source) is communicated by the amounts of transcription factors that it expresses (the message) to modulate the state of the promoter and expression levels of another gene (the receptor). The reliability of the gene network dynamics can be quantified by Shannon's entropy of the message and the mutual information between the message and the promoter state. Here we consider a stochastic model for a binary gene and use its exact steady state solutions to calculate the entropy and mutual information. We show that a slow switching promoter with long and equally standing ON and OFF states maximizes the mutual information and reduces entropy. That is a binary gene expression regime generating a high variance message governed by a bimodal probability distribution with peaks of the same height. Our results indicate that Shannon's theory can be a powerful framework for understanding how bursty gene expression conciliates with the striking spatio-temporal precision exhibited in pattern formation of developing organisms.
- Stochastic modeling for investigation of the regulation of transcription of the RKIP gene(2020) RAMOS, A. F.; GAMA, L. dos Reis; MORAIS, M. C. C. de; MARTINS, P. C. de MeloThe plethora of intracellular compounds interacting in well-orchestrated networks of chemical reactions, and the unavoidable randomness caused by low copy numbers of reactants, are main characteristics of the intracellular environment. That results on a huge amount of possible interactions and points out a major difficulty of employing the currently available experimental techniques to understand cellular behavior. In general, well controlled experiments deal with few elements selected accordingly with a set of biological principles to describe, categorize, and predict the dynamics of a biological system. However, those mostly qualitative principles may be insufficient for understanding some cellular phenomena and the application of theoretical tools usually developed within the scope of physics, mathematics, statistics, and computer sciences that might provide additional insights for cancer biologists. In this chapter, we present a stochastic approach to the regulation of gene transcription using a constitutive and binary stochastic model. We present the exact solutions for those models and introduce a framework for using those models in a treatment context targeting the regulation of gene expression. A discussion on the limitations of our approach and on the possible biological scenarios to which it applies is presented aiming at the design of therapeutic strategies changing Raf kinase inhibitory protein (RKIP) expression levels. © 2020 Elsevier Inc. All rights reserved.
- A Stochastic Binary Model for the Regulation of Gene Expression to Investigate Responses to Gene Therapy(2022) GIOVANINI, Guilherme; BARROS, Luciana R. C.; GAMA, Leonardo R.; TORTELLI, Tharcisio C.; RAMOS, Alexandre F.Simple Summary Gene editing technologies reached a turning point toward epigenetic modulation for cancer treatment. Gene networks are complex systems composed of multiple non-trivially coupled elements capable of reliably processing dynamical information from the environment despite unavoidable randomness. However, this functionality is lost when the cells are in a diseased state. Hence, gene-editing-based therapeutic design can be viewed as a gene network dynamics modulation toward a healthy state. Enhancement of this control relies on mathematical models capable of effectively describing the regulation of stochastic gene expression. We use a two-state stochastic model for gene expression to investigate treatment response with a switching target gene. We show the necessity of modulating multiple gene-expression-related processes to reach a heterogeneity-reduced specific response using epigenetic-targeting cancer treatment designs. Our approach can be used as an additional tool for developing epigenetic-targeting treatments. In this manuscript, we use an exactly solvable stochastic binary model for the regulation of gene expression to analyze the dynamics of response to a treatment aiming to modulate the number of transcripts of a master regulatory switching gene. The challenge is to combine multiple processes with different time scales to control the treatment response by a switching gene in an unavoidable noisy environment. To establish biologically relevant timescales for the parameters of the model, we select the RKIP gene and two non-specific drugs already known for changing RKIP levels in cancer cells. We demonstrate the usefulness of our method simulating three treatment scenarios aiming to reestablish RKIP gene expression dynamics toward a pre-cancerous state: (1) to increase the promoter's ON state duration; (2) to increase the mRNAs' synthesis rate; and (3) to increase both rates. We show that the pre-treatment kinetic rates of ON and OFF promoter switching speeds and mRNA synthesis and degradation will affect the heterogeneity and time for treatment response. Hence, we present a strategy for reaching increased average mRNA levels with diminished heterogeneity while reducing drug dosage by simultaneously targeting multiple kinetic rates that effectively represent the chemical processes underlying the regulation of gene expression. The decrease in heterogeneity of treatment response by a target gene helps to lower the chances of emergence of resistance. Our approach may be useful for inferring kinetic constants related to the expression of antimetastatic genes or oncogenes and for the design of multi-drug therapeutic strategies targeting the processes underpinning the expression of master regulatory genes.
- Myokines in treatment-na & iuml;ve patients with cancer-associated cachexia(2021) CASTRO, Gabriela S. de; CORREIA-LIMA, Joanna; SIMOES, Estefania; ORSSO, Camila E.; XIAO, Jingjie; GAMA, Leonardo R.; GOMES, Silvio P.; GONCALVES, Daniela Caetano; COSTA, Raquel G. F.; RADLOFF, Katrin; LENZ, Ulrike; TARANKO, Anna E.; BIN, Fang Chia; FORMIGA, Fernanda B.; GODOY, Louisie G. L. de; SOUZA, Rafael P. de; NUCCI, Luis H. A.; FEITOZA, Mario; CASTRO, Claudio C. de; TOKESHI, Flavio; ALCANTARA, Paulo S. M.; OTOCH, Jose P.; RAMOS, Alexandre F.; LAVIANO, Alessandro; COLETTI, Dario; MAZURAK, Vera C.; PRADO, Carla M.; SEELAENDER, MariliaCancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-na & iuml;ve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways. (c) 2020 The Author(s).
- Post-COVID-19 condition: systemic inflammation and low functional exercise capacity(2024) CASTRO, Gabriela Salim de; GAMA, Leonardo R.; RAMOS, Alexandre Ferreira; SILVA, Guilherme Gatti da; TEIXEIRA, Alexandre Abilio de Souza; CUNHA-NETO, Edecio; SOUZA, Heraldo Possolo de; MARIE, Suely K.; TALIB, Leda L.; COELHO, Veronica; KALIL, Jorge; ARAUJO, Adriana Ladeira de; RITTO, Ana Paula; BELON, Alessandro Rodrigo; SANTOS, Amanda Soares; BARRERE, Ana Paula Noronha; SAWAMURA, Marcio V. Y.; LAMAS, Celina Almeida; BALDI, Bruno Guedes; CARVALHO, Carlos R. R.; KULIKOWSKI, Leslie Domenici; DAMIANO, Rodolfo Furlan; IMAMURA, Marta; ROSA NETO, Jose Cesar; LIRA, Fabio S.; OTOCH, Jose Pinhata; MIGUEL, Euripedes Constantino; BATTISTELLA, Linamara; FORLENZA, Orestes V.; BUSATTO, Geraldo; SEELAENDER, MariliaIntroduction Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported.Methods In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment.Results SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-alpha 2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1 beta serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.